Jo Waters, Daily Mail, May 30, 2023
Rachel Hawley was 63 when she began noticing minor memory problems.
‘They were little things, such as repeating myself — people would say I’d told them things before — and struggling to remember recipes I’d cooked for years,’ she says.
‘It was nothing dramatic — my partner didn’t really notice anything — but it was enough for me to go to see my doctor.’
Her GP referred her to a memory clinic where she underwent cognitive tests and later a brain scan which revealed amyloid plaque in her brain — a build-up of proteins associated with Alzheimer’s disease.
The diagnosis was mild early-stage Alzheimer’s.
‘It was very depressing,’ says Rachel, 70, a retired social worker, who lives in North London with her partner Steven, 68, an architect.
The couple have two grown-up daughters and two grandsons.
Steven recalls her being quite philosophical. He says: ‘The day after, she was saying she’d had a really good life — while one of our daughters sobbed beside her on the sofa.’
But Rachel was one of the lucky ones — she read a newspaper article about a trial for a new drug that targeted amyloid plaque and she contacted a nurse at the hospital involved and joined the trial in late 2016.
At first, she was not told if she was receiving the drug (called aducanumab) or a placebo treatment — but she was willing to take that chance.
As it turned out, not only did Rachel receive the active drug but she was also in the high-dose group (there were also low-dose and placebo groups).
At one point early on in her treatment she experienced a side-effect called Aria (amyloid-related imaging abnormalities), which led to swelling in the brain, causing headaches, so she had to stop taking the pills temporarily.
But this lasted only a few weeks and she went back on the trial.
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Aducanumab (brand name Aduhelm) is the first of a new type of disease-modifying class of drugs for Alzheimer’s.
These work by removing amyloid plaque, a build-up of proteins that damage brain cells, which is closely linked with the disease.
Aduhelm was approved by the U.S. medicines regulator, the Food and Drug Administration (FDA), in June 2021, under an accelerated approval scheme, on the basis that it showed amyloid plaque was reduced by the drug and it was reasonably likely to have a clinical benefit.
But while it is now available in the U.S., Aduhelm is not without controversy.
The European Medicines Agency reviewed the evidence last year and said that the drug was unlikely to be approved in Europe if an application was made by the drug’s maker Biogen, on the basis that the clinical benefit was not proven (i.e. it hadn’t been shown that reducing amyloid stopped patients’ symptoms worsening), and there were concerns over safety (side-effects can include brain swelling and bleeding).
The company withdrew its application for approval in Europe in April 2022, although longer-term safety studies are ongoing, including the trial that Rachel is on.
But in the past few months, trial results for two more drugs — lecanemab and donanemab — which also target amyloid plaque, have been more promising.
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The three new drugs all contain antibodies that attach to amyloid and remove it.
The choice of amyloid as the target is based on work done in the UK by Professor Sir John Hardy, a neurogeneticist of University College London, who in 1991 led a team that uncovered the first genetic mutation directly implicated in Alzheimer’s.
This led to the theory that a build-up of amyloid is one of the causes of Alzheimer’s.
Since then, targeting amyloid plaque has been one of the main areas of drug research.
Lecanemab was approved by the FDA in January and is now available in the U.S. While there has been no application for the drug to be licensed in the UK as yet, the National Institute for Health and Care Excellence (NICE) has already begun a consultation on its effectiveness.
So have we reached the tipping point in the race to find a cure for Alzheimer’s?
Professor Hardy told Good Health: ‘Previous drugs have prevented further build-up [of amyloid], but these are the first to remove it.
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‘The effects are modest over an 18-month period.
‘What we need to understand now is what happens when people are on it for longer, and who is going to get good results and who isn’t.’
There are more than 140 Alzheimer’s drugs in the pipeline — 21 at the phase III level (where a drug is tested on a large number of people and compared with a control group) — and recent breakthroughs look promising.
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Other researchers are looking at the role of inflammation in the brain and of hormones in protecting the brain against damage. There are also new drugs being developed for controlling symptoms, including the first ever drug for agitation associated with Alzheimer’s — brexpiprazole (brand name Rexulti) was approved by the FDA this month.
Donanemab and lecanemab may get approval in the UK within 18 months to two years, according to some estimates.
But there are a number of barriers ahead.
Some experts have argued that the benefits of the Alzheimer’s drugs are modest and may not outweigh the risk of serious side-effects — for example, the risk of brain swelling in a brain-related disease is clearly a concern.
And there are more practical questions, about whether the NHS even has the capacity to deliver the MRIs, PET scans and lumbar punctures that will be needed to diagnose patients early and then monitor them while taking these new medicines (to check for side‑effects) — and also whether there are enough neurologists and psychiatrists to make early diagnoses.
And with the new drugs predicted to cost upwards of £20,000 a year per patient, can the UK afford to foot the massive drugs bill at a time when the NHS is already overstretched?
The most common side-effect of these drugs seen in trials is Aria, which can lead to swelling and bleeding in the brain and, in rare cases, stroke.
Aria occurred in approximately 40 per cent of participants in phase three studies of aducanumab and approximately a quarter of these experienced symptoms (including headache, confusion, dizziness and nausea).
In the latest results from the donanemab trial, the Aria-E rates (which is temporary brain swelling) were 24 per cent, with 6 per cent experiencing symptoms and 34 per cent had ARIA-H (i.e. microhaemorrhages).
Although the majority of cases were mild to moderate and resolved, 1.6 per cent of participants in this donanemab trial had serious ARIA — and three people died.
Whether there’s enough evidence that benefits outweigh the risks to justify the huge costs is proving to be an issue in the U.S. too, where the Centers for Medicare & Medicaid Services, which provides health coverage for millions of people, has refused to fund lecanemab and aducanumab, despite both drugs having FDA approval.
Dr Diana Zuckerman, president of the U.S. National Center for Health Research, a non-profit think tank, is yet to be convinced there’s enough evidence of the clinical benefits from amyloid-targeting drugs.
‘It’s a debatable point as to whether they even work at all,’ she told Good Health.
She says that people have died in the three trials — three after having a stroke (a bleed on the brain) and being put on blood thinners and then bleeding. (Although the maker, Biogen, has said none of the three deaths reported on the Aduhelm trial were caused by the drug.)
‘We need to have all the data to help people make the right decisions about these drugs — whether, for instance, they want to risk having a brain bleed — especially if they have any type of cardiac problem, which a lot of people in their 70s and 80s do, says Dr Zuckerman.
‘They don’t want to risk dying if they only have mild cognitive impairments that might go away with other activities that don’t involve drugs with risks like this.’
Another challenge will be getting an early diagnosis, as the drugs have so far been proven to work only in early-stage Alzheimer’s.
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Meanwhile, the PET scans needed to monitor amyloid and tau in the brain are mainly concentrated in the so-called ‘golden triangle’ of research centres between London, Oxford and Cambridge, says Dr Sara Imarisio, head of research at the charity Alzheimer’s Research UK. ‘We also need more staff trained to monitor how patients are reacting to the drugs,’ she adds.
Experts say it’s important to manage expectations, too — the new drugs have so far only been tested in early-stage Alzheimer’s. Dr Mummery says to give the drugs safely in the beginning, doctors will likely have to manage treatment in the same way as a trial.
‘This means no patients on blood thinners [owing to a risk of a brain bleed], no patients with other co-morbidities [other diseases] that might add to the risks, and making sure patients are robust enough to deal with coming to hospital for infusions and other tests,’ she says.
‘What I see is a process where we are cautious about who we give these drugs to at first.’
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